title: CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth.
abstract: CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38(MAPK), a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21(CIP1/WAF1). These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yae
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Motohara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ikeda
authors.forename: Rika
authors.initials: R
authors.lastname: Asaba
authors.forename: Hideki
authors.initials: H
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Kai
authors.forename: Eri
authors.initials: E
authors.lastname: Takahashi
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D021122:Protein Subunits; C118895:SLC7A11 protein, human